Glycogen storage disease type Ia (GSD-Ia or von Gierke disease, MIM232200) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), an enzyme that is expressed primarily in the liver, kidney, and intestine (Chou et al., Nat Rev Endocrinol 6:676-688, 2010). G6Pase-α, encoded by the G6PC gene, is a hydrophobic protein anchored in the endoplasmic reticulum (ER) by nine transmembrane helices (Chou et al., Nat Rev Endocrinol 6:676-688, 2010). This enzyme catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate in the terminal step of glycogenolysis and gluconeogenesis. Patients affected by GSD-Ia are unable to maintain glucose homeostasis and present with fasting hypoglycemia, growth retardation, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic academia (Chou et al., Nat Rev Endocrinol 6:676-688, 2010).
There is currently no cure for GSD-Ia. Hypoglycemia can be managed using dietary therapies (Greene et al., N Engl J Med 294:423-425, 1976; Chen et al., N Engl J Med 310:171-175, 1984) that enable patients to attain near normal growth and pubertal development. However, the longer term clinical complications, and their underlying pathological processes, remain uncorrected. One of the most significant chronic risks is hepatocellular adenoma (HCA), that develops in 70-80% of GSD-I patients over 25 years old (Chou et al., Nat Rev Endocrinol 6:676-688, 2010; Labrune et al., J Pediatr Gastroenterol Nutr 24:276-279, 1997; Rake et al., Eur J Pediatr 161(Suppl 1):520-S34, 2002). HCAs in GSD-Ia patients are small, multiple, and nonencapsulated, with complications including local compression and intratumoral hemorrhage. In 10% of GSD-Ia patients, HCAs undergo malignant transformation to hepatocellular carcinoma (HCC) (Chou et al., Nat Rev Endocrinol 6:676-688, 2010; Rake et al., Eur J Pediatr 161(Suppl 1):S20-S34, 2002; Franco et al., J Inherit Metab Dis 28:153-162, 2005).
Although gene therapy studies using recombinant adeno-associated virus (AAV) carrying G6Pase-α have previously been performed in animal models of GSD-Ia, none have been capable of completely correcting hepatic G6Pase-α deficiency. Thus, a need exists for an improved gene therapy vector for the treatment of GSD-Ia and its associated complications.